1. Field
The present methods and compositions relate to the field of Peyronie's disease, arteriosclerosis and other fibrotic conditions. More particularly, the method and compositions concern use of phosphodiesterase (PDE) inhibitors and modulators of nitric oxide, reactive oxygen species and metalloproteinases in the treatment of such conditions. In particular embodiments, the inhibitors inhibit type 4 and/or type 5 PDEs.
2. Description of Related Art
Peyronie's disease (PD) is a fibromatosis (Hellstrom and Bivalacqua, 2000; Schwarzer et al., 2001; Jarow et al., 1997; Devine et al., 1997) of the tunica albuginea (TA), the specialized lining of the corpora cavernosa of the penis. Clinically, this usually leads to penile deformation (curved penis during erection), pain, and quite frequently erectile dysfunction. The initiating event is believed to be an external force to the erect penis that results in an injury to the TA of the corpora and the TA fails to heal normally (Jarow et al., 1997; Devine et al., 1997; Diegelmann, 1997; Sherratt and Dallon, 2002). In the detumesced state, the only indication of the disease is the palpation of a knot or scar within the TA, which in its most severe state presents as a calcified plaque.
PD affects about 5% of men in the USA, and translating into about 3-4 million affected American males. Although the condition is not always associated with erectile dysfunction, patients usually present to the physician with either recognition of a palpable plaque on the penile shaft, pain with tumescence, impotence and/or difficulty with intromission that is due to curvature of the erect penis. Since the disorder was first described in 1743, no medical treatment has ever proven to be beneficial in combating the condition, thereby highlighting the need to develop novel approaches to combat this disorder.
There may also be a genetic predisposition to developing PD, since it is associated with other contractures such as Dupuytren's disease (palmar fascia; 10-20% incidence or more in PD) (Connelly, 1999) and Ledeshore's disease (plantar fascia). The pathophysiology is characterized by localized disruption of the TA, increased microvascular permeability, persistent fibrin (deficient fibrinolysis) and collagen deposition, perivascular inflammation, disorganization and loss of elastic fibers (release of elastase by macrophages), disorganized collagen bundles, and an increase in TGF-β1 synthesis. This represents impairment in the repair process that leads to persistent fibrosis and a loss of elasticity of the TA.
PD can rarely be alleviated by medical treatment with anti-inflammatory agents (corticosteroids, antihistamine), antioxidants (vitamin E, superoxide dismutase), collagen breakdown (collagenase), Ca channel blockers (verapamil), and other antifibrotic compounds (colchicine, Potaba: K aminobenzoate) (Hellstrom and Bivalacqua, 2000). In most cases, surgery is the only available option to correct the deformity and alleviate the pain so that normal sexual activity can be resumed. A need exists for non-surgical methods of treatment of Peyronie's disease and other medical conditions in which fibrosis is important.
Fibrotic disease is not limited to the reproductive organs, but can be found in other tissues, such as cardiovascular tissues. Both erectile dysfunction (ED) and cardiovascular disease, particularly hypertension, are prevalent in the aging male (Kloner et al., 2002; Sullivan et al., 2001; Melman et al., 1999). One of the underlying causes of hypertension is arteriosclerosis, or arterial stiffness, due to an acquired fibrosis of the media of the arterial wall (Breithaupt-Grogler and Belz, 1999; Robert, 1999; Intengan and Schiffrin, 2000, 2001; Formieri et al., 1992). Arteriosclerosis is significantly associated with aging, and is recognized by an increase in collagen, and in some cases by a loss of smooth muscle cells (SMC) within the arterial media, which results in a decrease in the SMC/collagen ratio, often accompanied by endothelial dysfunction (Cai and Harrison, 2000).
The pathogenesis of aging associated ED, both in the human and rat, is mostly related to the loss of SMC in the penile corpora cavernosa by apoptosis, with a corresponding increase in collagen fibers (Melman and Gingell, 1999; Cai and Harrison, 2000; Melman, 2001; Garban et al., 1995; Ferrini et al., 2001a). The clinical result of this aging process in the penis is defective cavernosal SMC relaxation leading to veno-occlusive dysfunction (Breithaupt-Grogler and Belz, 1999; Rogers et al., 2003), the most common cause of ED.
In the arterial tree, excessive collagen deposition in the media, with or without loss of SMC, leads to defective vaso-relaxation and clinically may present as hypertension (Breithaupt-Grogler and Belz, 1999; Robert, 1999; Intengan and Schiffrin, 2000, 2001). Because the penis may be considered a specialized extension of the vascular tree, the common alterations observed in the SMC of both the penis and peripheral vascular system in the aging male, leading to ED and hypertension, respectively, suggest that both conditions may share a common etiology.
A need exists for effective methods to treat and/or ameliorate the symptoms of a variety of fibrotic disease, such as PD, ED and arteriosclerosis. No effective method of treatment currently exists that is directed towards the molecular pathways underlying excessive collagen deposition.